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Cite this: DOI: 10.1039/x0xx00000x

Received 00th January 2012,

Accepted 00th January 2012

DOI: 10.1039/x0xx00000x

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A dual stimuli responsive fluorescent probe carrier

from double hydrophilic block copolymer capped with

β-cyclodextrin

Guang Yang,a Zhen Yang,

b Chengguang Mu,

b Xiaodong Fan,

b Wei Tian*

b and Qing

Wang* a

A double hydrophilic block copolymer with β-cyclodextrin

endgroups was prepared via RAFT polymerization and click

reaction. The micelle formation of the polymer has been

investigated as a function of temperature and pH values. The

release of the encapsulated fluorescent probe pyrene from the

polymer can be controlled by variation of temperature and

addition of adamantanyl-NH3Cl.

Introduction

Stimuli responsive polymers are able to change their chain

conformation, solubility, and intermolecular association in the

presence of external stimulations such as temperature,1 electrical

field,2 pH,3 redox agents,4, 5 and ionic strength.6 Especially,

responsive block copolymers have been widely studied because of

their ability to self-assemble into micelles with hydrophobic core

and hydrophilic shell during stimulation. These soft materials have

been reported to have promising biomedical applications such as

controlled drug and gene delivery, tissue engineering, and enzyme

catalysis.7-9 Stimuli responsive double hydrophilic block copolymers

(DHBCs) are capable of forming various types of aggregates such as

random aggregates, micelles, and more organized structure.10-13

DHBCs typically contain thermosensitive blocks such as poly(N-

isopropyl acrylamide) (PNIPAM)14 and polypropylene oxide,15 pH

sensitive blocks such as poly(2-(diethylamino)ethyl methacrylate)

(PDEA)11 and poly(4-vinyl-pyridine),16 or combination of

thermosensitive and pH sensitive blocks.17 PNIPAM is one of the

most popular thermoresponsive polymers with phase transition

temperature at 32 °C which is the result of entropy driven process of

hydrophobic interactions between the isopropyl groups. Among pH

sensitive polymers, PDEA is water-insoluble at neutral or alkaline

pH, but becomes soluble at pH<6.5 due to protonation of tertiary

amine residues.17 Solution properties of diblock copolymer

(PDEAEMA-b-PNIPAM) with tunable hydrophilicity has been

previously investigated.18

β-Cyclodextrin (β-CD), with hydrophilic exterior and hydrophobic

interior, is a native cyclic oligomer composed of 7 glucopyranose

units linked by α-1, 4-glycosidic bonds.19 The hydrophobic cavity

has been extensively utilized to serve as a host unit to construct host-

guest delivery carriers and supramolecular assemblies.20, 21 Over the

past few years, the combination of β-CD with stimuli-responsive

polymers to form nanoscale micelles as drug carriers has gained a lot

of attention.20-24 β-CD can be attached to one end of linear polymer

chains or serve as side groups of polymer chains while the assembly

process takes place via inclusion complexation between β-CD

moieties and other selected hydrophobic molecules bonded to

polymer chains. For instance, Liu et al. reported the preparation of β-

CD capped linear polymer β-CD-PNIPAM that was able to form

complexation with adamantane capped pH responsive polymer Ad-

PDEA in which the supramolecular diblock polymer had reversible

micelle to vesicle transition behavior.14 Zou et al. demonstrated that

the inclusion complexation between the azobenzene group and β-CD

unit at the end of linear polymer β-CD-PNIPAM could lead to

vesicle formation tuned by light and temperature.25 Linear polymer

chains with both ends capped by β-CD are new building blocks for

self-assemble process. Guo et al. reported the polyetherimide (PEI)

with β-CD at the both ends in which PEI can self-assemble into

vesicles in water. The vesicles were active in supramolecular

chemistry because the β-CDs were equally distributed on both

surfaces of the vesicles and adamantine-ended polyethylene glycol

could non-covalently form inclusion complexes with β-CD.23

Although responsive block copolymers have been used as

potential drug carriers and β-CD has been employed to modify the

chain end of non-responsive homopolymer, no study has been

performed on bonding β-CD to responsive DHBCs. We hypothesize

that if the chain ends of stimuli responsive DHBCs are modified

with β-CD, the polymer not only retain the multi-responsive

properties but also have functional end groups that can be used for

further assembly and modification. This may help to construct new

structures of polymer assemblies and drug carrier species. Herein we

report the synthesis and characterization of a dual stimuli-responsive

DHBC capped with β-CD that can be loaded with a fluorescent

probe at the both chain ends. The responses of the prepared block

copolymer with β-CD terminal groups to variation of temperature

and pH value have been investigated. Furthermore, we successfully

demonstrated that the fluorescent probe can be released from the

block copolymer by adding adamantanyl group containing molecules

that have extremely high complexation constant with β-CD.26

The synthetic route employed for the triblock copolymer PDEA-b-

PNIPAM-b-PDEA is illustrated in Scheme 1. The first step was to

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synthesize PDEA macro-chain transfer agent. As earlier noted,

PDEA is a pH sensitive hydrophilic polymer (pKa=7.3), which is

insoluble in neutral and alkaline solution. When pH is below 6.5,

PDEA is able to dissolve in water due to the protonation of the

tertiary amine to form a polycation. Dialysis process was thus

employed to purify PDEA and PDEA-b-PNIPAM-b-PDEA. Figure 1

shows the 1H NMR spectrum of PDEA-b-PNIPAM-b-PDEA that

confirmed the presence of PNIPAM and PDEA blocks. The

polymerization conditions and results were summarized in Table S1

(see Supporting Information). We initially designed a molar ratio of

DEA to NIPAM 30:65. Molecular weight measurements (Mn. SEC)

using size exclusion chromatography/multi angle light scattering

(SEC/MALLS) revealed that the ratio of DEA to NIPAM was 23:58,

demonstrating the theoretical molecular weight (Mn. Theo, 10.6k) was

slightly less than Mn. SEC (11.1k, PDI: 1.14). While Mn. Theo is based

on the assumption that all chains contain one trithiocarbonate

molecule, the difference between Mn. SEC and Mn. Theo can be

explained by production of a small number of dead chains due to

radical-radical termination.27 Gaussian approximation revealed that

about 11% of macroinitiator did not initiate further polymerization.

Figure S1 (see Supporting Information) shows the differential

refractive index (DRI) curves of PDEA and PDEA-b-PNIPAM-b-

PDEA and supports the Mn. SEC results.

Scheme 1. Synthesis of CD-PDEA-b-PNIPAM-b-PDEA-CD.

Figure 1. 1H NMR spectrum of PDEA-b-PNIPAM-b-PDEA.

Next, we modified the chain ends of the triblock copolymer

PDEA-b-PNIPAM-b-PDEA with propargylamine to yield the

alkynyl group, and then incorporated the β-CD molecules to the

PDEA-b-PNIPAM-b-PDEA chain ends by using click reaction

(Scheme 1).22 Considering the steric hindrance effect of β-CD that

may inhibit the click reaction, reaction temperature was raised above

room temperature.

Figure 2. A) FTIR spectra of (a) PDEA, (b) PDEA-b-PNIPAM-b-PDEA ,and (c) CD-PDEA-b-PNIPAM-b-PDEA-CD.

1H NMR spectra of B) pg-

PDEA-b-PNIPAM-b-PDEA-pg and C) CD-PDEA-b-PNIPAM-b-PDEA-CD.

Fourier transform infrared spectroscopy (FTIR) spectroscopy was

used to identify the structures of PDEA, PDEA-b-PNIPAM-b-

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PDEA, and CD-PDEA-b-PNIPAM-b-PDEA-CD (Figure 2A). For

PDEA (curve a), the wavenumber at 1730 cm-1 can be assigned to

the C=O stretching vibrational absorption of PDEA and 1254 cm-1

belongs to C-N stretching vibrational absorption. For PDEA-b-

PNIPAM-b-PDEA (curve b), absorption at 1554 cm-1 comes from N-

H bending vibration of NIPAM and 1643 cm-1 arises from C=O

absorption of NIPAM. In the case of CD-PDEA-b-PNIPAM-b-

PDEA-CD (curve c), absorptions at 1080 cm-1 and 1031 cm-1 are

attributable to C-O and C-O-C stretching vibrational absorption in β-

CD, respectively. Also, the peak at 1062 cm-1 belongs to C=S

bending vibrational absorption that results from the PDEA macro-

chain transfer agent. 1H NMR was used to characterize the structure

of pg-PDEA-b-PNIPAM-b-PDEA-pg (pg stands for propargyl

group) (Figure 2B) and CD-PDEA-b-PNIPAM-b-PDEA-CD (Figure

2C). As shown in Figure 2B, chemical shift δ at 1.92 was assigned to

the proton of alkynyl group at both ends of polymer chain while the

chemical shift δ at 5.15-5.25 in Figure 2C was resulted from protons

of cyclodextrin units. 1H NMR results revealed that β-CD molecules

were successfully bonded to polymer chain end via click reaction. It

is estimated that 33% of the chain ends are functionalized.

Liu et al. synthesized diblock copolymer PDEA-b-PNIPAM

using RAFT method and found that the low critical solution

temperature (LCST) of this polymer was pH dependent (25 ℃ at

pH=8 and 34 ℃ at pH=6).28 In this study due to the presence of

PDEA and CD, we hypothesized that the LCSTs of PDEA-b-

PNIPAM-b-PDEA and CD-PDEA-b-PNIPAM-b-PDEA-CD were

higher than the LCST of PNIPAM. Figure 3A shows the UV

transmittance as a function of temperature for PDEA-b-PNIPAM-b-

PDEA and CD-PDEA-b-PNIPAM-b-PDEA-CD. The LCST of

PDEA-b-PNIPAM-b-PDEA was about 36.6 ℃, which was obviously

higher than that of PNIPAM, i.e. 32 ℃ because the hydrogen bond

between the triblock copolymer and solution was strengthened when

hydrophilic PDEA was incorporated into the copolymer.29

Consequently, the hydrophilic component made it difficult for the

triblock copolymer to dehydrate when temperature was raised.30 For

CD-PDEA-b-PNIPAM-b-PDEA-CD, the LCST value was about 37

℃; this can be explained by the hydrophilic feature of β-CD, which

made polymer phase transition more difficult.

We characterized the Z-average particle size (Dz) change of self-

assembled aggregates as a function of temperature and pH using

dynamic laser scattering (DLS). Before DLS measurement, PDEA

was completely dissolved in hydrochloric acid solution to avoid

chain aggregation in the solution.18 Figure 3B shows the change in

Dz of CD-PDEA-b-PNIPAM-b-PDEA-CD and PDEA-b-PNIPAM-

b-PDEA as a function of temperature. In the case of CD-PDEA-b-

PNIPAM-b-PDEA-CD, Dz ranged between 190 to 200 nm at low

temperature (i.e. <34 ℃). As the temperature increased above 34 ℃,

the Dz quickly increased and was stable at 240 nm, indicating the

self-assemble process that was induced by the coil to globe transition

of PNIPAM chain. Figure 3B also demonstrates a similar Dz trend

for PDEA-b-PNIPAM-b-PDEA. Interestingly, the Dz remained

between 130 and 137 nm at temperatures below 33 ℃ and increased

to 192 nm as the temperature increased. These results revealed that

the presence of β-CD units increased the Dz value.

We also characterized the changes of Dz of self-assembled

aggregates for CD-PDEA-b-PNIPAM-b-PDEA-CD group as a

function of pH values (Figure 3C). At pH<6, Dz decreased from 215

to 173 nm, however, as pH increased beyond 7, the Dz significantly

dropped to 121 nm and finally was stabilized at 105 nm, indicating

the self-assemble process that was induced by the hydrophobic

transition of PDEA chain. Figure 3C also presents the Dz for PDEA-

b-PNIPAM-b-PDEA as a function of pH. For pH<8, the Dz slightly

decreased from 135 to 129 nm, however, as pH elevated beyond 8 an

obvious decrease took place and finally the Dz was finally stable at

100 nm. The difference in trend of Dz as a function of pH and

temperature might be explained by different self-assembly process in

ABA triblock copolymers when block A becomes hydrophobic (pH

induced) and block B becomes hydrophobic (temperature induced).31

Figure 3. A) UV transmission change curves of PDEA-b-PNIPAM-b-PDEA and CD-PDEA-b-PNIPAM-b-PDEA-CD (pH=4). B) Dz as a function of temperature for (a) CD-PDEA-b-PNIPAM-b-PDEA-CD, and (b) PDEA-b-PNIPAM-b-PDEA (pH=4, 0.1 mg mL

-1). C) Dz as a function of pH for (a) CD-PDEA-b-PNIPAM-b-

PDEA-CD, and (b) PDEA-b-PNIPAM-b-PDEA (0.1 mg mL-1

, 25 ℃). D) Dz distribution of CD-PDEA-b-PNIPAM-b-PDEA-CD solution (0.1 mg mL

-1) (a)

pH=4, 39 ℃, (b) pH=4, 25 ℃, (c) pH=11, 25 ℃. E) Fluorescence excitation spectra of pyrene in the presence of CD-PDEA-b-PNIPAM-b-PDEA-CD (pH=4, 25 ℃). F) CMC determination of CD-PDEA-b-PNIPAM-b-PDEA-CD (pH=4, 25 ℃). G) I1/I3 ratio from emission spectra of pyrene in the presence of (a) PDEA-b-PNIPAM-b-PDEA and (b) CD-PDEA-b-PNIPAM-b-PDEA-CD. (pH=4, 0.1 mg�mL

-1). H) I1/I3 ratio from emission spectra of pyrene in the presence of

PDEA-b-PNIPAM-b-PDEA, CD-PDEA-b-PNIPAM-b-PDEA-CD, and CD as a function of Ada-NH3�Cl concentration (the inset graph shows the emission peaks I1 and I3 at 0.04 mg/mL of Ada-NH3�Cl).

Figure 3D shows the diameter distribution of CD-PDEA-b-

PNIPAM-b-PDEA-CD self-assembled aggregates at different

temperature and pH. When PNIPAM chain underwent phase

transition and PDEA chain remained soluble (pH=4, 39 ℃), the Dz

was 241 nm (red curve) and particle dispersion index (PDI) was

0.122. When both PDEA and PNIPAM chains were soluble in water

(pH=4, 25 ℃) the Dz was reduced to 213 nm and PDI was 0.228

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(black curve). When PDEA chain underwent phase transition but

PNIPAM remained soluble in water (pH=11, 25 ℃), the Dz value

further decreased to 104 nm and PDI was 0.151 (green curve). The

PDI values were in the range of 0.08-0.70, indicating that the

particles’ size had mid-range polydispersity.32 Zeta potential was

used to study the stability of colloids. When the absolute value of

zeta potential is higher than 30 mV, the dispersion is stable.33 Figure

S2 (see Supporting Information) shows the zeta potential of CD-

PDEA-b-PNIPAM-b-PDEA-CD as a function of temperature in an

acidic solution. The zeta potential value was ~52 mV at the

beginning when the temperature was lower than 35 ℃, then

increased quickly as temperature was elevated above 35 ℃ at the

rate of 0.2 ºC min-1. Finally it was significantly slowed down after

41 ℃. It could be inferred that these particles were stably dispersed

in the solution.

Other group reported that DHBC would form micelles in solution

when one block of DHBC became hydrophobic.34 As indicated in

Figure 3A, the LCST of CD-PDEA-b-PNIPAM-b-PDEA-CD was

determined to be about 37 ℃. Therefore, there was no thermal

induced micelle formation of PDEA-b-PNIPAM-b-PDEA at 25 ℃.

However, after bonding with β-CD we detected the micelle

formation using fluorescence spectroscopy of probe molecule

pyrene. Polymer was dissolved in 6×10-6 M pyrene solution with

different concentrations. As depicted in Figure 3E, the fluorescence

intensity increased as the polymer concentration increased from

0.0001 to 10 mg mL-1. There was a shift of the (0, 0) absorption

band from 335 to 337 nm, indicating the formation of micelles.35 In

addition, the plot of fluorescence intensity ratio of I337/I335 as a

function of concentration (Figure 3F) further elucidates the critical

micelle concentration (CMC) value to be 0.036 mg mL-1. We

previously found that β-CD became less hydrophilic after mono-

substitution modification.36 It is possible that the presence of β-CD

served as relatively hydrophobic units and induced the micelle

formation.

The encapsulation of pyrene molecule into CD-PDEA-b-

PNIPAM-b-PDEA-CD was investigated using fluorescence

spectroscopy. The intensity of the first emission peak to the third

emission peak ratio (I1/I3) can be used to characterize the micro-

environment of pyrene. The smaller I1/I3 value indicates the more

hydrophobic environment for the pyrene molecule.37 The

hydrophobic cavity of β-CD can encapsulate pyrene molecule by

forming complexation of pyrene into β-CD.38 To minimize the

disturbing effect of encapsulated pyrene, and make sure that the

complexation process of pyrene into β-CD was in equilibrium, the

pyrene/polymer solution was kept at room temperature for 1 day

before measurement.23 As shown in Figure 3G, at low temperature

pyrene was in hydrophilic environment and I1/I3 was stable. As

temperature increased above 34 ℃, there was a sharp decrease,

indicating that pyrene molecules were in more hydrophobic area due

to the phase transition of PNIPAM chain. Finally, I1/I3 maintained at

a stable value, indicative of the equilibrium of pyrene/PNIPAM

interaction. It has been reported that hydrophobic adamantanyl (Ada)

group and β-CD could be used for drug release experiments because

of their significantly higher inclusion constant (5×104 M-1) compared

with other guest molecules.21, 23 In order to further explore the

functionality of the β-CD end groups, Ada-NH3·Cl was added to the

solution at 45 ℃. As indicated in Figure 3H, as the concentration of

Ada-NH3·Cl increased from 0 to 0.1 mg/mL, the value of I1/I3

increased steadily for CD-PDEA-b-PNIPAM-b-PDEA-CD group.

However, for the group without β-CD the I1/I3 value showed no

obvious change when the Ada-NH3·Cl was added. The increase of

I1/I3 can be inferred that for the CD-PDEA-b-PNIPAM-b-PDEA-CD

group more pyrene molecules were expelled out of β-CD cavities to

the hydrophilic environment by adding Ada-NH3·Cl. In the group

without β-CD, there were no β-CD units and nothing can be replaced

by Ada-NH3·Cl, thus I1/I3 value did not change. Also, it seems that

pyrene exchange with CD-PDEA-b-PNIPAM-b-PDEA-CD is less

efficient than the exchange with pristine CD.

Conclusions

In summary, the β-CD terminated triblock copolymer CD-PDEA-b-

PNIPAM-b-PDEA-CD with both hydrophilic temperature

(PNIPAM) and pH (PDEA) responsive chains have been synthesized

via RAFT polymerization and subsequent click reaction. Unique

thermo and pH sensitive properties have been demonstrated in CD-

PDEA-b-PNIPAM-b-PDEA-CD micelles when compared to PDEA-

b-PNIPAM-b-PDEA. The diameter distribution (PDI) of these

polymeric nanoparticles in the solution was found to be in the mid-

range polydispersity. Pyrene molecules are encapsulated in the

polymer assemblies and β-CD cavities and can be released by adding

Ada-NH3·Cl molecules. We envision the extension of the strategy

reported here as a proof of concept to develop novel

drugs/biomolecules encapsulated β-CD terminated triblock

copolymer. With enormous potential for sensing, tissue engineering,

and drug delivery systems, we believe this technique can be used for

different applications in sensors, scaffolding and other biomedical

areas.

Acknowledgements

The authors are grateful to the National Natural Science Foundation

of China (NO. 21374088) for financial support. W. Tian thanks the

grant from the Program for New Century Excellent Talents of

Ministry of Education (NCET-13-0476), the Program of Youth

Science and Technology Nova of Shaanxi Province of China

(2013KJXX-21), and the Program of New staff and Research Area

Project of NPU (13GH014602).

Notes and references a Department of Materials Science and Engineering, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. E-mail:

wang@matse.psu.edu b The key lab of Space Applied Physics and Chemistry, Ministry of

Education and Shaanxi Key Lab of Macromolecular Science and

Technology, School of Science, Northwestern Polytechnical University, Xi’an 710072, Shaanxi, China

† Electronic Supplementary Information (ESI) available: synthesis, structure characterization. See DOI: 10.1039/c000000x/

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